The immune response to highly pathogenic viruses such as influenza, is a double edged sword. In response to influenza infection, innate and adaptive immune components coordinate elimination of the pathogen from the lung; however, these same processes can generate pathological reactions including excessive cytokine production and destruction of lung airways now believed to be the leading cause of death and pneumonia from the 1918 pandemic influenza (H1N1) and avian influenza (H5N1) strains. This dual nature of the immune response, with the ability to promote protection and immunopathology, is well-documented in diverse viral systems, suggesting that immunomodulating strategies that promote a protective or beneficial immune response while suppressing an undesired immune response would be an ideal treatment strategy for new pandemic influenza strains. However, mechanisms for the immunopathology observed in adult immune responses to influenza and strategies to regulate such responses remain unknown. My laboratory has developed a novel mouse model in which immunity to influenza is driven by memory CD4 T cells, that also has significant clinical relevance given that most older children and adults have been exposed to influenza and can maintain memory T cells to invariant viral determinants, and that ample number of memory T cells reside in the lung and can therefore provide a "first-line" response at the site of infection. We have found that memory CD4 T cells can coordinate both protective and pathologic responses to influenza manifested by rapid viral clearance in the presence of extensive lung immune infiltration and tissue damage -features not observed in flu-infected naive mice lacking specific memory T cells. We also have obtained preliminary evidence that the CD28 costimulatory pathway may be instrumental in controlling this bipartite nature of the memory CD4 T cell response to influenza, in that blocking CD28 costimulation with the inhibition reagent CTLA4Ig maintains protection while lessening the lung damage and weight-loss pathology observed during infection. In the proposed research, we will build on these interesting preliminary findings to delve into the mechanism for memory CD4 T cell-induced immunopathology during influenza challenge, and how interfering with the CD28 costimulatory pathway on memory CD4 T cells may be the optimal immunomodulator for enhancing protection while abrogating immunopathology. Given the clinical relevance of examining memory T cell responses to influenza as a model for adult immune responses, and the fact that CTLA4Ig is already used clinically to lessen immunopathology in rheumatoid arthritis, the proposed research could lead to a readily translatable strategy for regulating deleterious immune responses to virulent pathogens via modulation of memory T cells. [unreadable] [unreadable] [unreadable]